Cabozantinib Plus Atezolizumab or Cabozantinib Alone in Patients With Advanced NSCLC Previously Treated With an Immune Checkpoint Inhibitor: Results From the Phase 1b COSMIC-021 Study

Introduction We evaluated efficacy and safety of cabozantinib plus atezolizumab or cabozantinib alone in advanced NSCLC previously treated with an immune checkpoint inhibitor (ICI). Methods COSMIC-021 (NCT03170960) is a phase 1b, multicenter study in advanced solid tumors. This analysis included patients with stage IV non-squamous NSCLC without actionable genomic aberrations in EGFR, ALK, ROS1, or BRAF-V600E who progressed on one prior ICI and less than or equal to two prior lines of systemic anticancer therapy. Patients received cabozantinib 40 mg orally/day plus atezolizumab 1200 mg intravenously every three weeks (combination cohort) or cabozantinib 60 mg orally/day (single-agent cabozantinib cohort). Primary end point of the combination cohort was objective response rate per Response Evaluation Criteria in Solid Tumors v1.1 by investigator. Outcomes in the single-agent cabozantinib cohort were exploratory. Results Eighty-one patients assigned to combination therapy and 31 assigned to single-agent cabozantinib received greater than or equal to one dose of study treatment. Median (range) follow-up was 26.1 months (12.1–44.2) and 22.4 months (1.5–29.0), respectively. Objective response rate was 20% (95% confidence interval: 11.7%–30.1%) in combination cohort and 6% (95% confidence interval: 0.8%–21.4%) in single-agent cabozantinib cohort. Treatment-related adverse events (TRAEs) occurred in 86% of patients in the combination cohort and 90% in the single-agent cabozantinib cohort; grade 3/4 TRAEs were 44% and 48%, respectively. There were two grade 5 TRAEs: pneumonitis (n = 1, combination) and gastric ulcer hemorrhage (n = 1, single-agent). Neither PD-L1 expression in tumor cells nor tumor mutation burden correlated with outcomes. Conclusions Cabozantinib plus atezolizumab demonstrated modest clinical activity and manageable toxicity in advanced NSCLC after progression on prior ICI.


Introduction
First-line anti-PD-L1/PD-1 immune checkpoint inhibitors (anti-PD-(L)1 ICIs) with or without chemotherapy are standard of care for patients with advanced NSCLC without actionable genomic aberrations. 1,2Anti-PD-(L)1 ICIs are also the standard of care for patients with advanced NSCLC who progressed on platinumbased chemotherapy. 2However, despite advances in immunotherapy, the vast majority of patients with NSCLC experience disease progression, [3][4][5][6] and effective treatment options after progression on anti-PD-(L)1 ICIs are needed. 7,86][7] In a phase 2 trial, the combination of ramucirumab with the PD-1 inhibitor pembrolizumab demonstrated a survival benefit versus standard of care in patients with advanced NSCLC after progression on prior ICIs. 7Therefore, the combination of a VEGF pathway-targeting agent with an ICI may help overcome resistance to ICIs.
Cabozantinib is a tyrosine kinase inhibitor (TKI) that targets multiple receptor tyrosine kinases, including MET, VEGFR, and the TAM family of kinases (TYRO3, AXL, MER), and has the potential to enhance response to ICIs. 9 Cabozantinib in combination with ICIs has demonstrated efficacy in renal cell carcinoma and hepatocellular carcinoma in phase 3 studies. 10,11Atezolizumab is an anti-PD-L1 monoclonal antibody approved as monotherapy or in combination with chemotherapy for first-line treatment of advanced NSCLC with no EGFR or ALK genomic tumor aberrations. 6COSMIC-021 is a phase 1b study evaluating cabozantinib in combination with atezolizumab in multiple advanced solid tumors.Reported here are results in patients with advanced NSCLC who progressed following prior ICI therapy, treated with either cabozantinib plus atezolizumab (expansion combination cohort) or single-agent cabozantinib (exploratory single-agent cabozantinib cohort).

Study Design and Participants
COSMIC-021 is a multicenter, open-label, phase 1b study with a dose-escalation stage and a subsequent tumor-specific cohort expansion stage.The doseescalation stage evaluated cabozantinib 40 mg and 60 mg in combination with atezolizumab and has been previously reported. 12The recommended dose of the combination for the cohort-expansion stage was cabozantinib 40 mg orally once daily plus atezolizumab 1200 mg intravenously every 3 weeks.Following the doseescalation stage, patients were enrolled into tumorspecific cohorts in an expansion stage.Patients with NSCLC who were previously treated with an anti-PD-(L) 1 ICI therapy were enrolled into two cohorts and treated with either cabozantinib plus atezolizumab (combination cohort) or single-agent cabozantinib (single-agent cabozantinib cohort).
For both cohorts, eligible patients were greater than or equal to 18 years of age with stage IV non-squamous NSCLC with radiographic progression on or after one prior anti-PD-(L)1 ICI therapy for metastatic disease.Patients were required to have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate organ and marrow function, and availability of tumor tissue.Patients could have received up to two prior lines of systemic anticancer therapy to treat metastatic NSCLC (an anti-CTLA-4 agent was allowed; prior platinum-based chemotherapy was not required).Prior treatment with a VEGFR-targeting TKI was not allowed.Patients with tumors harboring known EGFR, ALK, ROS1, or BRAF V600E aberrations were excluded.Radiation therapy was not allowed within four weeks (two weeks for bone metastases) prior to study treatment initiation.Brain metastases must have been treated and stable for greater than or equal to four weeks before the first dose of study treatment.Patients with uncontrolled, significant intercurrent or recent illness were excluded.
This study adhered to the Good Clinical Practice guidelines and the Declaration of Helsinki.The study was approved by the institutional review board at each study center, and all patients provided written informed consent.This study was registered with ClinicalTrials.gov,NCT03170960.

Procedures
Patients in the combination cohort received cabozantinib 40 mg orally once daily plus atezolizumab 1200 mg intravenously every three weeks, while patients in the single-agent cabozantinib cohort received single-agent cabozantinib 60 mg orally once daily; patients in the single-agent cabozantinib cohort who progressed on single-agent cabozantinib could cross over to receive the addition of atezolizumab.The first 51 patients were enrolled in a non-randomized fashion into the combination cohort to assess the clinical activity of the combination.Subsequent patients were randomized 1:1 to the combination or single-agent cohort using an unstratified permuted block design.Patients were treated until lack of clinical benefit, need for subsequent systemic anticancer treatment, or unacceptable toxicity.Treatment could be continued after radiographic progression if there was clinical benefit as determined by the investigator.Dose delays of cabozantinib and atezolizumab and dose reductions of cabozantinib (up to three reductions for single-agent cabozantinib cohort and two for combination cohort; 60 mg-40 mg daily, 40 mg-20 mg daily, 20 mg daily-20 mg every other day) were allowed to manage adverse events (AEs); dose reductions of atezolizumab were not allowed.
Tumor assessments by computed tomography or magnetic resonance imaging were performed per RECIST v1.1 by the investigator every six weeks for the first 12 months, then every 12 weeks thereafter.
Safety, including AE severity, relationship to study treatment, and relationship to immune effects, was assessed by the investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0.
Peripheral blood and tumor tissues were collected for exploratory biomarker analyses.Archival tumor tissue was obtained as formalin-fixed paraffin-embedded tumor blocks, or if unavailable, tumor slides.Fresh tumor tissue biopsies were optional.When available, blood samples were used to evaluate plasma, serum, and cellular biomarkers, and tumor tissue samples were used to evaluate changes in biomarker expression and genetic/genomic aberrations, but these assessments were not required.Tumor mutation burden (TMB), presence of genomic mutations (KRAS, STK11, KEAP1, or STK11), and PD-L1 expression in tumor cells were evaluated as follows for their effect on tumor response, OS, and progression-free survival (PFS).PD-L1 was assayed centrally (by Ventana SP263 assay, Roche Diagnostics, Florham Park, NJ) for patients with tumor samples available; other patients had PD-L1 status determined by the investigator or had unknown status.Formalin-fixed paraffin-embedded tumor tissue used in immunohistochemistry analyses and matched blood samples were used for whole exome sequencing to determine TMB.A DNA library was generated from fragmented genomic DNA using Agilent SureSelectXT Human all Exon 50 Mb v6 capture baits (Agilent, Santa Clara, CA) and sequenced by sequencing-by-synthesis technology (SBS, Illumina, San Diego, CA) with a read depth of 250Â for tumor tissue and 50Â for blood samples.TMB was calculated by excluding germline variants, variants with a maximum population frequency of greater than 0.1% in the 1000 genomes project (National Heart Lung and Blood Institute Grand Opportunity Exome Sequencing Project or gnomAD), and variants that failed the variant quality filter.Variant calls were restricted to include only variants located within high confidence regions of protein coding sequence.

End Points and Assessments
The primary end point of the combination cohort was objective response rate (ORR; defined as the proportion of patients who achieved a confirmed partial or complete response as best response) per RECIST v1.1 by investigator.The secondary end point was safety through evaluation of AEs, serious AEs, and AEs of special interest (AESIs; immune-mediated AEs associated with ICIs, cases of potential drug-induced liver injury, and suspected transmission of an infectious agent by the study treatment).Exploratory end points included the following: duration of response (DOR; defined as the time between first observed tumor response and subsequent first occurrence of disease progression or death) and PFS (defined as time from first dose to the earlier of radiographic progression or death from any cause) by investigator per RECIST v1.1; ORR, DOR, and PFS by blinded independent radiology committee (BIRC) per RECIST v1.1; OS (defined as time from first dose to death from any cause); and biomarker analyses.
End points of the single-agent cabozantinib cohort were exploratory and included all efficacy and safety analyses conducted for the combination cohort (except subgroup analyses), and biomarker analyses.

Statistical Analysis
All analyses were conducted in the safety population, which is defined as all patients who received any study treatment.Continuous data were summarized using descriptive statistics; categorical data were summarized using frequencies and percentages.ORR per RECIST v1.1 was evaluated with a two-sided 95% exact binomial confidence interval (CI), using the Clopper-Pearson method.Median DOR, PFS, OS, and associated 95% CIs were estimated using the Kaplan-Meier method.Exploratory modeling analyses including survival analysis with time-dependent covariates, general linear models, and mixed models with repeated measures were employed to assess relationships between biomarker measurements and ORR, PFS, and OS.Maximum percent tumor reduction from baseline in target lesions was assessed based on patients in the safety population.All analyses were conducted using SAS version 9.3 or higher (SAS Institute, Cary, NC).

Patients
Between April 2018 and December 2020, 112 patients with NSCLC who were enrolled in the combination cohort (n ¼ 81) and the single-agent cabozantinib cohort (n ¼ 31) received at least one dose of study treatment and were included in the safety population (Fig. 1).Median age (range) was 67 years (38-93) in the combination cohort and 70 years (48-92) in the single-agent cabozantinib cohort.Most patients had an ECOG performance status of 1 (64% [52 of 81] for the combination cohort; 71% [22 of 31] for the single-agent cabozantinib cohort; Table 1).
Within each cohort, nearly equal proportions of patients received one and two prior lines of systemic anticancer therapy for locally advanced or metastatic disease, 35 patients (43%) and 45 patients (56%) in the combination cohort and 14 patients (45%) and 14 patients (45%) in the single-agent cabozantinib cohort, respectively.Prior platinum-containing chemotherapy was received by 65 patients (80%) in the combination cohort and 24 patients (77%) in the single-agent cabozantinib cohort.Prior anti-PD-(L)1 ICI treatment was received without prior chemotherapy by 14 patients (17%) in the combination cohort and five patients (16%) in the single-agent cabozantinib cohort; concurrently with platinum-containing chemotherapy by 29 patients (36%) and 11 patients (35%); following platinumcontaining chemotherapy by 31 patients (38%) and 11 patients (35%); and prior to platinum-containing chemotherapy by two patients (2%) and one patient (3%).In the combination cohort, the best response to prior anti-PD-(L)1 ICI therapy was complete response in one patient (1%), partial response in 14 patients (17%), stable disease in 35 patients (43%), and progressive disease in 22 patients (27%); in the single-agent cabozantinib cohort, the best response to prior anti-PD-(L)1 ICI therapy was partial response in six patients (19%),  stable disease in seven patients (23%), and progressive disease in 13 patients (42%).
The median (range) duration of follow-up was 26.1 months (12.1-44.2) in the combination cohort and 22.4 months (1.5-29.0) in the single-agent cabozantinib cohort.At the data cutoff, five of 81 patients (6%) in the combination cohort and seven of 31 patients (26%) in the singleagent cabozantinib cohort remained on study treatment.The most common reason for treatment discontinuation was progressive disease in both cohorts (53% [43 of 81] in combination cohort and 48% [15 of 31] in single-agent cabozantinib cohort; Fig. 1).Subsequent therapy was received by 24 patients (30%) in the combination cohort and six (19%) in the single-agent cabozantinib cohort (not including patients who crossed over to cabozantinib plus atezolizumab; Supplementary Table 1).
Median DOR per RECIST v1.1 by investigator was 5.8 months (95% CI: 4.2-6.9) in the combination cohort (Table 2).DOR in the combination cohort was similar across subgroups by ECOG PS, PD-L1 status, and response to prior ICI (Supplementary Table 3).Seventy-two percent (58 of 81) of evaluable patients in the combination cohort and 58% (18 of 31) of evaluable patients in the singleagent cabozantinib cohort had any reduction in target lesions from baseline (Fig. 2).Change in sum of target lesions over time per RECIST v1.1 by investigator is shown in Supplementary Figure 1.Of the patients in the combination cohort remaining on cabozantinib plus atezolizumab treatment at data cutoff, three had an ongoing partial response and one of these patients had been treated for more than 27 months (Supplementary Figure 2).In the single-agent cabozantinib cohort, both patients who achieved a partial response with cabozantinib had discontinued treatment (one patient at w10 months, and the other at w16 months).

Safety
At the data cutoff, median (range) duration of study treatment exposure was 5.2 months (0.3-30.2) in the combination cohort and 3.5 months (0.7-16.4) in the single-agent cabozantinib cohort (Supplementary Table 4).Treatment-emergent AEs occurred in all patients in each cohort (Supplementary Table 5) and led to dose modification of cabozantinib (delays or dose reductions) in 77% of patients in the combination cohort and 87% in the single-agent cabozantinib cohort.Treatment-emergent AEs led to delay of atezolizumab in 33% in the combination cohort.
Treatment-related AEs (TRAEs) occurred in 86% of patients in the combination cohort and 90% of patients in the single-agent cabozantinib cohort (Table 3).The most common of these included diarrhea (40% in combination cohort and 42% in single-agent cabozantinib cohort), fatigue (28% and 19%), decreased appetite (25% and 23%), nausea (22% and 42%), and asthenia (22% and 32%).Grade 3/4 TRAEs occurred in 44% in the combination cohort and 48% in the single-agent cabozantinib cohort.The most frequent included hypertension (4% in combination cohort and 19% in single-agent cabozantinib cohort) and asthenia (4% and 6%).TRAEs leading to discontinuation of cabozantinib were reported in 15% in the combination cohort and 6% in the single-agent cabozantinib cohort; those leading to discontinuation of atezolizumab were reported in 11% in the combination cohort.There was one treatmentrelated grade 5 event in each cohort: pneumonitis in combination cohort and gastric ulcer hemorrhage (patient was receiving concomitant anticoagulation) in the single-agent cabozantinib cohort.

Biomarkers
There was no significant correlation between any of the assessed biomarkers (TMB, PD-L1 expression in tumor cells, and KRAS, STK11, or KEAP1/STK11 mutations) and tumor response, OS, or PFS.PD-L1 data are shown in Supplementary Table 3, and other biomarker data are shown in Supplementary Figures 4 and 5.
or progressive disease as best response to their prior ICI treatment, suggesting that the addition of a TKI may facilitate resensitization to ICIs.In this study, no clear association was found between biomarkers assessed (TMB, PD-L1 status, presence of KRAS, STK11, or KEAP1/ STK11 mutations) and response, PFS, or OS, indicating that the ICI plus TKI combination may benefit a heterogeneous patient population.
In addition to cabozantinib plus atezolizumab, other vascular endothelial growth factor pathway agents have been evaluated in combination with ICIs following prior immunotherapy.The phase 2 Lung-MAP S1800A study evaluated ramucirumab in combination with pembrolizumab versus standards of care, including ramucirumab plus docetaxel and single-agent chemotherapy, in patients with advanced NSCLC who previously received immunotherapy. 7ORR, PFS, and OS with cabozantinib plus atezolizumab in COSMIC-021 were similar to those reported with ramucirumab plus pembrolizumab.However, it is important to note that differences in the patient population between the studies limit any comparisons of outcomes.Although the ramucirumab plus pembrolizumab study enrolled patients with acquired resistance to ICI within at least 84 days after ICI treatment initiation, our study did not select patients based on type of ICI resistance.In addition, patients in the ramucirumab plus pembrolizumab study had squamous or non-squamous NSCLC; our study included only patients with non-squamous NSCLC.
Based on encouraging clinical activity observed in the current analysis, cabozantinib plus atezolizumab was further evaluated in patients with NSCLC in the phase 3 CONTACT-01 study.Patients in CONTACT-01 had metastatic NSCLC that was non-squamous (75%) or squamous (25%) and had progressed after an anti-PD-(L)1 ICI therapy in combination with or subsequent to chemotherapy.The study did not meet its primary end point of OS with cabozantinib plus atezolizumab versus docetaxel (median 10.7 months for the combination versus 10.5 months for docetaxel). 15It is worth noting that differences in study populations limit comparisons between CONTACT-01 and COSMIC-021; COSMIC-021 only included patients with non-squamous NSCLC, and progression on prior platinumcontaining chemotherapy was not an eligibility requirement (81% received prior chemotherapy).
One limitation of this analysis of COSMIC-021 was that it was not designed for direct comparison of cabozantinib plus atezolizumab versus single-agent cabozantinib, and different starting doses of cabozantinib were used in each cohort (40 mg in the combination cohort, 60 mg in the single-agent cabozantinib cohort).In addition, it is notable that the investigator-assessed ORR for combination therapy was double that of the BIRC-assessed rate, which is consistent with prior reports showing that investigators tend to overestimate the ORR compared with BIRC. 16In addition, the study was limited by sample size, and the cabozantinib plus atezolizumab cohort was comprised of non-randomized and randomized patients (patients were initially enrolled into the combination cohort to assess clinical activity, and subsequent patients were randomized to the combination cohort or single-agent cabozantinib cohort).Biomarker analyses were also limited by the small number of patients in each analysis.
Other phase 3 studies have also evaluated the role of TKIs in combination with ICIs versus standard-of-care chemotherapy in patients with NSCLC who progressed on prior immunotherapy (LEAP-008 [NCT03976375]; SAPPHIRE [NCT03906071]). 17,18These studies did not meet their primary end point of improving OS. 17,18 More detailed information from these studies may help with the design of future clinical trials in this difficult-to-treat patient population.
In conclusion, cabozantinib plus atezolizumab demonstrated modest clinical activity in patients with advanced non-squamous NSCLC who progressed on prior anti-PD-(L)1 ICI therapy.Clinical activity was observed regardless of ECOG PS, prior response to ICIs, or PD-L1 status.Safety was consistent with the known safety profiles of the individual agents.None of the evaluated biomarkers were associated with outcomes.There remains an unmet need to improve on the longstanding standard of cytotoxic chemotherapy in the treatment of NSCLC that is refractory to immunotherapy and platinum-based chemotherapy.

Figure 1 .
Figure 1.Patient disposition.*The first 51 patients were enrolled in a non-randomized fashion into the cabozantinib þ atezolizumab cohort, and subsequent patients were randomized 1:1 between the cabozantinib þ atezolizumab and cabozantinib cohorts.

Figure 2 .
Figure 2. Waterfall plot for maximum percent change from baseline in target lesions per RECIST v1.1 by investigator in (A) combination cohort and (B) single-agent cabozantinib cohort.Maximum percentage of reduction or minimum increase from baseline in sum of diameters of target lesions before progressive disease or initiation of any non-protocol anticancer therapy.Only patients with at least one baseline and post-baseline radiographic tumor assessment are shown.Any reduction in the sum of diameter in target lesion was observed in 72% (58 of 81) of patients in the combination cohort and 58% (18 of 31) of patients in the single-agent cabozantinib cohort.PD-L1, programmed death-ligand 1; RECIST, Response Evaluation Criteria in Solid Tumors.

Table 1 .
Continued PD-L1 expression in tumor cells; based on central assessment using SP263 assay or local assessment per investigator.Three patients who reported having three lines of therapy were confirmed to have had 1 or 2 lines of therapy post data cutoff.CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitor; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; RECIST, Response Evaluation Criteria in Solid Tumors.
a Histology of two patients was missing in the combination arm.b c For locally advanced or metastatic disease.d